University of Groningen
Continuous intraperitoneal insulin infusion in the treatment of type 1 diabetes mellitusvan Dijk, Peter R.
IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.
Document VersionPublisher's PDF, also known as Version of record
Publication date:2015
Link to publication in University of Groningen/UMCG research database
Citation for published version (APA):van Dijk, P. R. (2015). Continuous intraperitoneal insulin infusion in the treatment of type 1 diabetesmellitus: Glycaemia and beyond. [S.n.].
CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).
Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.
Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.
Download date: 13-08-2021
78 79
Van Dijk PR, Logtenberg SJ, Groenier KH, Feenstra J, Gans RO,
Bilo HJ, Kleefstra N.
Intraperitoneal insulin infusion is non-inferior to subcutaneous
insulin infusion in the treatment of type 1 diabetes: a prospec-
tive matched-control study.
chapter 5 Abstract
introductionContinuous intraperitoneal insulin infusion (CIPII) using an implantable pump is a last-
resort treatment option for patients with type 1 diabetes mellitus (T1DM) who fail to reach
glycaemic control with intensified subcutaneous (SC) insulin regimens. Aim of this study was
to compare the effects of CIPII with SC insulin therapy in T1DM.
patients and methodsProspective, observational matched-control study. Patients were eligible if they had been
treated with either CIPII or SC insulin for > 4 years and had a HbA1c of ≥ 7.0%. CIPII treated
cases were matched to SC treated controls regarding age and gender. Primary endpoint
was a non-inferiority assessment (pre-defined margin of -0.5%) of the difference in HbA1c
during a 26-week interval between both groups. Analysis were performed with ANCOVA,
taking baseline differences into account.
resultsDuring study, one patient withdrew consent. Subsequently 183 patients with a mean age
of 50 years (standard deviation (SD) 12) and a diabetes duration of 26 years (SD 13) were
analysed. Of these, 39 were treated with CIPII and 144 with SC insulin therapy. Age and
gender were well matched. HbA1c remained stable within the CIPII group while it decreased
with -0.09% (95% confidence interval (CI) -0.17, -0.01) in the SC group. The difference
between treatment groups was -0.27% (95% CI -0.46, -0.09) and met the predefined non-
inferiority criterion. During continuous glucose sensor use, patients using SC insulin therapy
spend less time in hyperglycaemia (-9.3%, 95% CI -15.8, -2.8%) and more in euglycaemia
(6.9%, 95% CI 1.2, 12.5%) as compared to patients using CIPII. Besides a difference in alanine
aminotransferase (ALT) concentrations between groups of 3.6 U/l (95% CI 1.2, 6.0), being
lower in the CIPII group, no other biochemical or clinical differences were present.
conclusionCIPII therapy is non-inferior to SC insulin therapy with respect to HbA1c in the treatment of
poorly controlled T1DM patients. Besides a lower ALT among CIPII treated patients within
the normal range, there are no differences in clinical and biochemical parameters. This study
supports the long-term use of CIPII therapy as last-resort treatment in T1DM.
submitted as
Intraperitoneal insulin infusion is non-inferior to subcutaneous insulin infusion in the treatment of type 1 diabetes: a prospective mached- control study
chapter 5part 2
78 79
Van Dijk PR, Logtenberg SJ, Groenier KH, Feenstra J, Gans RO,
Bilo HJ, Kleefstra N.
Intraperitoneal insulin infusion is non-inferior to subcutaneous
insulin infusion in the treatment of type 1 diabetes: a prospec-
tive matched-control study.
chapter 5 Abstract
introductionContinuous intraperitoneal insulin infusion (CIPII) using an implantable pump is a last-
resort treatment option for patients with type 1 diabetes mellitus (T1DM) who fail to reach
glycaemic control with intensified subcutaneous (SC) insulin regimens. Aim of this study was
to compare the effects of CIPII with SC insulin therapy in T1DM.
patients and methodsProspective, observational matched-control study. Patients were eligible if they had been
treated with either CIPII or SC insulin for > 4 years and had a HbA1c of ≥ 7.0%. CIPII treated
cases were matched to SC treated controls regarding age and gender. Primary endpoint
was a non-inferiority assessment (pre-defined margin of -0.5%) of the difference in HbA1c
during a 26-week interval between both groups. Analysis were performed with ANCOVA,
taking baseline differences into account.
resultsDuring study, one patient withdrew consent. Subsequently 183 patients with a mean age
of 50 years (standard deviation (SD) 12) and a diabetes duration of 26 years (SD 13) were
analysed. Of these, 39 were treated with CIPII and 144 with SC insulin therapy. Age and
gender were well matched. HbA1c remained stable within the CIPII group while it decreased
with -0.09% (95% confidence interval (CI) -0.17, -0.01) in the SC group. The difference
between treatment groups was -0.27% (95% CI -0.46, -0.09) and met the predefined non-
inferiority criterion. During continuous glucose sensor use, patients using SC insulin therapy
spend less time in hyperglycaemia (-9.3%, 95% CI -15.8, -2.8%) and more in euglycaemia
(6.9%, 95% CI 1.2, 12.5%) as compared to patients using CIPII. Besides a difference in alanine
aminotransferase (ALT) concentrations between groups of 3.6 U/l (95% CI 1.2, 6.0), being
lower in the CIPII group, no other biochemical or clinical differences were present.
conclusionCIPII therapy is non-inferior to SC insulin therapy with respect to HbA1c in the treatment of
poorly controlled T1DM patients. Besides a lower ALT among CIPII treated patients within
the normal range, there are no differences in clinical and biochemical parameters. This study
supports the long-term use of CIPII therapy as last-resort treatment in T1DM.
submitted as
Intraperitoneal insulin infusion is non-inferior to subcutaneous insulin infusion in the treatment of type 1 diabetes: a prospective mached- control study
chapter 5part 2
80 81
Introduction
Treatment of type 1 diabetes mellitus (T1DM) consists of insulin administration or pancreas
(islet cells) transplantation. In most patients, insulin is administered subcutaneously (SC) using
multiple daily injections (MDI) or continuous subcutaneous insulin infusion (CSII) using an
external pump. Although most patients achieve acceptable glycaemic control using SC insulin
some patients fail to either reach adequate glycaemic control, some because of SC insulin
resistance, or have frequent hypoglycaemic episodes 1. Continuous intraperitoneal insulin
infusion (CIPII) with an implantable pump is a treatment option for such patients.
With CIPII, the SC environment is bypassed and the physiological route of insulin is mimicked
because intraperitoneal (IP) administered insulin diffuses into the portal vein catchment area.
Compared to SC insulin therapy, IP administered insulin results in higher hepatic insulin
uptake, alleviation of peripheral plasma insulin concentrations and a more rapid and
predictable insulin action 2–5. Of the three randomized clinical studies that compared CIPII with
SC insulin treatment in T1DM patients, two reported HbA1c improvements of 0.76% to 1.28%
without an increase in hypoglycaemic episodes and one did not find any differences between
therapies 6–8.
Since CIPII with an implantable pump is an invasive and costly treatment for selected patients,
there is a clear need for data regarding the long-term efficacy of CIPII as compared to SC insulin
therapy in order to justify the use of CIPII. However, available randomized studies have a short
duration and a small number of participants, and observational studies lack a control group 9,10.
Aim of this study was to compare the effects of long-term CIPII therapy with SC insulin therapy
among patients with poorly controlled T1DM.
Patients and methods
study designWe conducted an investigator initiated, prospective, observational matched-control study to
compare the effects on glycaemic control of CIPII versus SC insulin therapy. Patient recruitment
took place in two hospitals, the Isala (Zwolle, the Netherlands) and the Diaconessenhuis
hospital (Meppel, the Netherlands).
Since CIPII is as a last-resort treatment option for T1DM, CIPII treated patients are a highly
selected population with a rather complex background and disease history. In order to account
for this inequality between both treatment groups (CIPII versus SC insulin therapy), the
primary endpoint was a non-inferiority assessment of the difference in HbA1c during a
26-week period, taking possible baseline differences into account, between both groups.
patient selection Cases were subjects on CIPII therapy using an implanted insulin pump (MIP 2007D, Medtronic/
Minimed, Northridge, CA, USA) for the past 4 years without interruptions of >30 days, in order
to avoid effects related to initiating therapy. Inclusion criteria for cases were identical to those
of a prior study in our centre and have been described in detail previously 6. In brief, patients
with T1DM, aged 18 to 70 years with a HbA1c ≥ 7.5% and/or ≥ 5 incidents of hypoglycemia
glucose (< 4.0 mmol/l) per week, were eligible.
Controls using SC insulin therapy were selected from the outpatient clinic population.
Eligibility criteria were T1DM, MDI or CSII insulin as mode of insulin administration for the past
4 years without interruptions of >30 days, HbA1c ≥ 7.0% and proper knowledge of the Dutch
language.
Exclusion criteria for both cases and controls were: impaired renal function (plasma creatinine
≥150 µmol/l or glomerular filtration rate as estimated by the Cockcroft-Gault formula
≤50 ml/min, cardiac problems (unstable angina or myocardial infarction within the previous
12 months or New York Heart Association class III or IV congestive heart failure, cognitive
impairment, current or past psychiatric treatment for schizophrenia, cognitive or bipolar
disorder, current use of oral corticosteroids or suffering from a condition which necessitated
oral or systemic corticosteroids use more than once in the previous 12 months, substance
abuse, other than nicotine, current gravidity or plans to become pregnant during the study,
plans to engage in activities that require going >25 feet below sea level or any condition that
the investigator and/or coordinating investigator feels would interfere with study participation
or evaluation of results.
If patients were eligible to act as SC control, they were matched to the CIPII treated cases based
on gender and age. The SC control group consisted of both MDI and CSII users. The ratio of
participants on the different therapies (CIPII:MDI:CSII) was 1:2:2.
chapter 5part 2
80 81
Introduction
Treatment of type 1 diabetes mellitus (T1DM) consists of insulin administration or pancreas
(islet cells) transplantation. In most patients, insulin is administered subcutaneously (SC) using
multiple daily injections (MDI) or continuous subcutaneous insulin infusion (CSII) using an
external pump. Although most patients achieve acceptable glycaemic control using SC insulin
some patients fail to either reach adequate glycaemic control, some because of SC insulin
resistance, or have frequent hypoglycaemic episodes 1. Continuous intraperitoneal insulin
infusion (CIPII) with an implantable pump is a treatment option for such patients.
With CIPII, the SC environment is bypassed and the physiological route of insulin is mimicked
because intraperitoneal (IP) administered insulin diffuses into the portal vein catchment area.
Compared to SC insulin therapy, IP administered insulin results in higher hepatic insulin
uptake, alleviation of peripheral plasma insulin concentrations and a more rapid and
predictable insulin action 2–5. Of the three randomized clinical studies that compared CIPII with
SC insulin treatment in T1DM patients, two reported HbA1c improvements of 0.76% to 1.28%
without an increase in hypoglycaemic episodes and one did not find any differences between
therapies 6–8.
Since CIPII with an implantable pump is an invasive and costly treatment for selected patients,
there is a clear need for data regarding the long-term efficacy of CIPII as compared to SC insulin
therapy in order to justify the use of CIPII. However, available randomized studies have a short
duration and a small number of participants, and observational studies lack a control group 9,10.
Aim of this study was to compare the effects of long-term CIPII therapy with SC insulin therapy
among patients with poorly controlled T1DM.
Patients and methods
study designWe conducted an investigator initiated, prospective, observational matched-control study to
compare the effects on glycaemic control of CIPII versus SC insulin therapy. Patient recruitment
took place in two hospitals, the Isala (Zwolle, the Netherlands) and the Diaconessenhuis
hospital (Meppel, the Netherlands).
Since CIPII is as a last-resort treatment option for T1DM, CIPII treated patients are a highly
selected population with a rather complex background and disease history. In order to account
for this inequality between both treatment groups (CIPII versus SC insulin therapy), the
primary endpoint was a non-inferiority assessment of the difference in HbA1c during a
26-week period, taking possible baseline differences into account, between both groups.
patient selection Cases were subjects on CIPII therapy using an implanted insulin pump (MIP 2007D, Medtronic/
Minimed, Northridge, CA, USA) for the past 4 years without interruptions of >30 days, in order
to avoid effects related to initiating therapy. Inclusion criteria for cases were identical to those
of a prior study in our centre and have been described in detail previously 6. In brief, patients
with T1DM, aged 18 to 70 years with a HbA1c ≥ 7.5% and/or ≥ 5 incidents of hypoglycemia
glucose (< 4.0 mmol/l) per week, were eligible.
Controls using SC insulin therapy were selected from the outpatient clinic population.
Eligibility criteria were T1DM, MDI or CSII insulin as mode of insulin administration for the past
4 years without interruptions of >30 days, HbA1c ≥ 7.0% and proper knowledge of the Dutch
language.
Exclusion criteria for both cases and controls were: impaired renal function (plasma creatinine
≥150 µmol/l or glomerular filtration rate as estimated by the Cockcroft-Gault formula
≤50 ml/min, cardiac problems (unstable angina or myocardial infarction within the previous
12 months or New York Heart Association class III or IV congestive heart failure, cognitive
impairment, current or past psychiatric treatment for schizophrenia, cognitive or bipolar
disorder, current use of oral corticosteroids or suffering from a condition which necessitated
oral or systemic corticosteroids use more than once in the previous 12 months, substance
abuse, other than nicotine, current gravidity or plans to become pregnant during the study,
plans to engage in activities that require going >25 feet below sea level or any condition that
the investigator and/or coordinating investigator feels would interfere with study participation
or evaluation of results.
If patients were eligible to act as SC control, they were matched to the CIPII treated cases based
on gender and age. The SC control group consisted of both MDI and CSII users. The ratio of
participants on the different therapies (CIPII:MDI:CSII) was 1:2:2.
chapter 5part 2
82 83
study proceduresThere were four study visits. During the first visit, baseline characteristics were collected using
a standardized case record form and a continuous glucose measurement (CGM) system was
inserted for a period of six days. During the second visit (five to seven days later) the CGM
system was removed and laboratory measurements were performed. During the third visit, 26
weeks after visit 1, clinical parameters were collected and again a CGM device was inserted for
a period of six days. During the fourth visit, five to seven days after the third visit, laboratory
measurements were performed and the CGM device was removed. During the study period all
patients received usual care.
measurementsDemographic and clinical parameters included: age, gender, weight, length, blood pressure,
smoking and alcohol habits, co-morbidities, medication use, year of diagnosis of diabetes,
presence of microvascular (nephropathy, neuropathy and/or retinopathy) or macrovascular
complications (angina pectoris, myocardial infarction, coronary artery bypass grafting,
percutaneous transluminal coronary angioplasty, stroke, transient ischemic attack, peripheral
artery disease), previous day insulin therapy (kind of insulin, dosage and, if applicable, the
number of daily injections) and the number of self-reported hypoglycaemic events grade 1
(<4.0 mmol/l), grade 2 (<3.5 mmol/l) and grade 3 (requiring third party help or losing
consciousness) during the last two weeks. Blood pressure was measured using a blood
pressure monitor (M6 comfort; OMRON Healthcare) using the highest mean of four
measurements (two on each arm). Laboratory measurements included hemoglobin (Hb),
creatinine, C-peptide, total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides,
albumin, fibrinogen, aspartate aminotransferase (AST), alanine aminotransferase (ALT),
y-glutamyl transpeptidase (gamma-GT), alkaline phosphatase and urine albumin/creatinine
ratio and HbA1c. HbA1c was measured with a Primus Ultra2 system using high-performance
liquid chromatography (reference value 4.0-6.0%). The six-day 24-hours interstitial glucose
profiles were recorded using a blinded CGM device (iPro2, Medtronic, Northridge, CA, USA).
The CGM device was inserted in the periumbilical area, and in pump users contralateral to
the (implanted) insulin pump. Patients injecting insulin were asked not to inject insulin on
the same side of the sensor insertion side. Patients were instructed to perform a minimum
of 4 blood glucose self-measurements daily during the CGM period, using a validated blood
glucose meter (Contour XT; Bayer) to calibrate the sensor. Time spent in hypoglycemia was
defined as the percentage of CGM readings <4.0 mmol/l, time spent in euglycemia was defined
as the percentage of CGM readings from 4.0 to 10.0 mmol/l, and time spent in hyperglycemia
was defined as the percentage of CGM readings >10.0 mmol/l.
outcome measuresThe primary outcome measure was the difference in HbA1c over a period of 26 weeks between
cases and controls adjusted for baseline differences. Secondary outcomes included differences
in clinical aspects, CGM measures and laboratory measurements between groups.
statistical analysisThe study was designed to test the hypothesis that CIPII would be non-inferior to SC insulin
therapy in T1DM patients during a 26-week follow-up period with respect to the primary
outcome measure. The criteria for non-inferiority required that the upper limits of the 95%
confidence intervals (CI) were above the predefined margin for the difference in HbA1c.
Based on the results of previous randomized clinical trials and discussion with experts, a
non-inferiority margin (Δ) of -0.5% was chosen 6–8. According to pre-specified protocol, both
per protocol and intention-to-treat analysis were performed. A regression model based on
covariate analysis (ANCOVA) was applied in order to take possible baseline imbalance in
HbA1c into account. In the model the fixed factors CIPII and SC insulin therapy were used
as determinants. The difference in scores was determined based on the b-coefficient of the
particular (CIPII or SC, MDI or CSII) group. Significance of the b-coefficient was investigated
with the Wald test based on a p<0.05. The quantity of the b-coefficient, with a 95% CI, gives
the difference between both treatment modalities over the study period adjusted for baseline
differences.
With the use of a standard deviation (SD) of 0.9%, estimated from the previous cross-over
study, and a non-inferiority margin of -0.5%, we calculated that we would need to enrol 175
patients (35 CIPII, 140 SC insulin therapy) to show non-inferiority of CIPII therapy at a one-sided
alpha level of 0.025 6. In order to compensate for loss-to-follow-up, intended group sample
sizes were 40 and 150, respectively.
Statistical analyses were performed using SPSS (IBM SPSS Statistics for Windows, Version 20.0.
Armonk, NY: IBM Corp.) and STATA version 12 (Stata Corp., College Station, TX: StataCorp LP).
Results were expressed as mean (with SD) or median (with the interquartile range [IQR]) for
normally distributed and non-normally distributed data, respectively. A significance level of
5% was used.
The study protocol was registered prior to the start of the study at the appropriate local
(NL41037.075.12) and international registers (NCT01621308). The study protocol was approved
by the local medical ethics committee and all patients gave informed consent.
chapter 5part 2
82 83
study proceduresThere were four study visits. During the first visit, baseline characteristics were collected using
a standardized case record form and a continuous glucose measurement (CGM) system was
inserted for a period of six days. During the second visit (five to seven days later) the CGM
system was removed and laboratory measurements were performed. During the third visit, 26
weeks after visit 1, clinical parameters were collected and again a CGM device was inserted for
a period of six days. During the fourth visit, five to seven days after the third visit, laboratory
measurements were performed and the CGM device was removed. During the study period all
patients received usual care.
measurementsDemographic and clinical parameters included: age, gender, weight, length, blood pressure,
smoking and alcohol habits, co-morbidities, medication use, year of diagnosis of diabetes,
presence of microvascular (nephropathy, neuropathy and/or retinopathy) or macrovascular
complications (angina pectoris, myocardial infarction, coronary artery bypass grafting,
percutaneous transluminal coronary angioplasty, stroke, transient ischemic attack, peripheral
artery disease), previous day insulin therapy (kind of insulin, dosage and, if applicable, the
number of daily injections) and the number of self-reported hypoglycaemic events grade 1
(<4.0 mmol/l), grade 2 (<3.5 mmol/l) and grade 3 (requiring third party help or losing
consciousness) during the last two weeks. Blood pressure was measured using a blood
pressure monitor (M6 comfort; OMRON Healthcare) using the highest mean of four
measurements (two on each arm). Laboratory measurements included hemoglobin (Hb),
creatinine, C-peptide, total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides,
albumin, fibrinogen, aspartate aminotransferase (AST), alanine aminotransferase (ALT),
y-glutamyl transpeptidase (gamma-GT), alkaline phosphatase and urine albumin/creatinine
ratio and HbA1c. HbA1c was measured with a Primus Ultra2 system using high-performance
liquid chromatography (reference value 4.0-6.0%). The six-day 24-hours interstitial glucose
profiles were recorded using a blinded CGM device (iPro2, Medtronic, Northridge, CA, USA).
The CGM device was inserted in the periumbilical area, and in pump users contralateral to
the (implanted) insulin pump. Patients injecting insulin were asked not to inject insulin on
the same side of the sensor insertion side. Patients were instructed to perform a minimum
of 4 blood glucose self-measurements daily during the CGM period, using a validated blood
glucose meter (Contour XT; Bayer) to calibrate the sensor. Time spent in hypoglycemia was
defined as the percentage of CGM readings <4.0 mmol/l, time spent in euglycemia was defined
as the percentage of CGM readings from 4.0 to 10.0 mmol/l, and time spent in hyperglycemia
was defined as the percentage of CGM readings >10.0 mmol/l.
outcome measuresThe primary outcome measure was the difference in HbA1c over a period of 26 weeks between
cases and controls adjusted for baseline differences. Secondary outcomes included differences
in clinical aspects, CGM measures and laboratory measurements between groups.
statistical analysisThe study was designed to test the hypothesis that CIPII would be non-inferior to SC insulin
therapy in T1DM patients during a 26-week follow-up period with respect to the primary
outcome measure. The criteria for non-inferiority required that the upper limits of the 95%
confidence intervals (CI) were above the predefined margin for the difference in HbA1c.
Based on the results of previous randomized clinical trials and discussion with experts, a
non-inferiority margin (Δ) of -0.5% was chosen 6–8. According to pre-specified protocol, both
per protocol and intention-to-treat analysis were performed. A regression model based on
covariate analysis (ANCOVA) was applied in order to take possible baseline imbalance in
HbA1c into account. In the model the fixed factors CIPII and SC insulin therapy were used
as determinants. The difference in scores was determined based on the b-coefficient of the
particular (CIPII or SC, MDI or CSII) group. Significance of the b-coefficient was investigated
with the Wald test based on a p<0.05. The quantity of the b-coefficient, with a 95% CI, gives
the difference between both treatment modalities over the study period adjusted for baseline
differences.
With the use of a standard deviation (SD) of 0.9%, estimated from the previous cross-over
study, and a non-inferiority margin of -0.5%, we calculated that we would need to enrol 175
patients (35 CIPII, 140 SC insulin therapy) to show non-inferiority of CIPII therapy at a one-sided
alpha level of 0.025 6. In order to compensate for loss-to-follow-up, intended group sample
sizes were 40 and 150, respectively.
Statistical analyses were performed using SPSS (IBM SPSS Statistics for Windows, Version 20.0.
Armonk, NY: IBM Corp.) and STATA version 12 (Stata Corp., College Station, TX: StataCorp LP).
Results were expressed as mean (with SD) or median (with the interquartile range [IQR]) for
normally distributed and non-normally distributed data, respectively. A significance level of
5% was used.
The study protocol was registered prior to the start of the study at the appropriate local
(NL41037.075.12) and international registers (NCT01621308). The study protocol was approved
by the local medical ethics committee and all patients gave informed consent.
chapter 5part 2
84 85
Results
patientsFrom December 2012 through August 2013, a total of 335 patients were screened and received
information about the study of which 190 agreed to participate. After baseline laboratory
measurements, six patients were excluded because of reasons presented in Figure 1.
Consequently, 184 patients were followed during the 26-week study period. After the first visit
one patient withdrew informed consent due to lack of interest. Therefore, 183 patients were
analysed.
Main baseline characteristics are presented in Table 1 and more detailed information is
provided in Appendix 1. Age and gender were well matched between groups. No grade 3
hypoglycaemic events were reported. Compared to patients using SC insulin therapy, CIPII
patients had a higher diastolic blood pressure, more microvascular complications, used
more units of insulin per day and spent less time in hypoglycaemic range and more time in
hyperglycaemic range during CGM recordings.
primary outcome - glycaemic controlWithin the group of CIPII treated patients, HbA1c did not significantly changed while it
decreased with -0.09% (95% CI -0.17, -0.01) among patients treated with SC insulin therapy
(see Table 2). Taking baseline differences into account, the difference between treatment
groups was -0.27% (95% CI -0.46, -0.09) and met the non-inferiority criterion of -0.5 % (see
Figure 2). The results of the intention-to treat analyses did not differ from the per-protocol
analysis (see Appendix 2). During study, the number of grade 1 hypoglycaemic episodes during
the last 2 weeks decreased with -1.2 (95% CI -1.7, -0.7) among patients with SC insulin. Patients
using SC insulin therapy spent less percentage of time in hyperglycemia (-9.3% (95% CI -15.8,
-2.8)) and more in euglycemia (6.9% (95% CI 1.2, 12.5) as compared to patients using CIPII.
secondary outcome - clinical and biochemical parametersDuring follow-up, three patients experienced a macrovascular complication: one patient
treated with CIPII had angina pectoris, one patient using MDI had a transient ischemic attack
and one patients using CSII had a myocardial infarction. In two patients a new microvascular
complication was diagnosed: one patient using MDI had nephropathy and patient using CSII
had retinopathy..There was a decrease in systolic blood pressure (-5.6 mmHg, 95% CI -11.0, -0.1)
and serum creatinin concentration (5.0 µmol/l, 95% CI 2.0, 7.5) over time among CIPII treated
patients. Among SC treated patients systolic blood pressure (-3.4 mmHg, 95% CI -6.5, -0.2)
decreased and BMI (0.2 kg/m2, 95% CI 0.0, 0.4) increased over time. Concentrations of ALT (2.6
U/l, 95% CI 1. 2, 4.0) and serum creatinine (3.2 µmol/l, 95% CI 2.2, 4.2) increased in SC treated
patients. Taking baseline differences into account, CIPII treated patients had significant lower
concentrations of ALT as compared to patients treated with SC insulin therapy: 3.6 U/l (95% CI
1.2, 6.0). The results of measurements of all clinical and biochemical parameters performed
at baseline and the end of the study and changes within and differences between groups are
presented in the Appendix 3.
chapter 5part 2
Patient flowchart.figure 1
eligible patients that received information (n=335)
included (n=190)
cipii therapy (n=40)sc insulin therapy (n=150)• mdi (n=75)• csii (n=75)
excluded after visit 2 (n=1)• egfr <40 ml/min
excluded after visit 2 (n=5)• c-peptide > 0.2 nmol/l (n=4)• egfr < 40 ml/min (n=1)
discontinued study (withdrew consent) (n=1)
completed study and included in analysis (n=144)• mdi (n=70)• csii (n=74)
completed study and included in analysis (n=39)
excluded (n=145)• not meeting inclusion criteria (n=11) - psychiatric illness (n=4) - hbA1c < 7.0% (n=3) - predison use (n=2) - non-compliant (n=1)• declined to participate (n=46)• not asked for participation due to logistic reasons (n=88)
84 85
Results
patientsFrom December 2012 through August 2013, a total of 335 patients were screened and received
information about the study of which 190 agreed to participate. After baseline laboratory
measurements, six patients were excluded because of reasons presented in Figure 1.
Consequently, 184 patients were followed during the 26-week study period. After the first visit
one patient withdrew informed consent due to lack of interest. Therefore, 183 patients were
analysed.
Main baseline characteristics are presented in Table 1 and more detailed information is
provided in Appendix 1. Age and gender were well matched between groups. No grade 3
hypoglycaemic events were reported. Compared to patients using SC insulin therapy, CIPII
patients had a higher diastolic blood pressure, more microvascular complications, used
more units of insulin per day and spent less time in hypoglycaemic range and more time in
hyperglycaemic range during CGM recordings.
primary outcome - glycaemic controlWithin the group of CIPII treated patients, HbA1c did not significantly changed while it
decreased with -0.09% (95% CI -0.17, -0.01) among patients treated with SC insulin therapy
(see Table 2). Taking baseline differences into account, the difference between treatment
groups was -0.27% (95% CI -0.46, -0.09) and met the non-inferiority criterion of -0.5 % (see
Figure 2). The results of the intention-to treat analyses did not differ from the per-protocol
analysis (see Appendix 2). During study, the number of grade 1 hypoglycaemic episodes during
the last 2 weeks decreased with -1.2 (95% CI -1.7, -0.7) among patients with SC insulin. Patients
using SC insulin therapy spent less percentage of time in hyperglycemia (-9.3% (95% CI -15.8,
-2.8)) and more in euglycemia (6.9% (95% CI 1.2, 12.5) as compared to patients using CIPII.
secondary outcome - clinical and biochemical parametersDuring follow-up, three patients experienced a macrovascular complication: one patient
treated with CIPII had angina pectoris, one patient using MDI had a transient ischemic attack
and one patients using CSII had a myocardial infarction. In two patients a new microvascular
complication was diagnosed: one patient using MDI had nephropathy and patient using CSII
had retinopathy..There was a decrease in systolic blood pressure (-5.6 mmHg, 95% CI -11.0, -0.1)
and serum creatinin concentration (5.0 µmol/l, 95% CI 2.0, 7.5) over time among CIPII treated
patients. Among SC treated patients systolic blood pressure (-3.4 mmHg, 95% CI -6.5, -0.2)
decreased and BMI (0.2 kg/m2, 95% CI 0.0, 0.4) increased over time. Concentrations of ALT (2.6
U/l, 95% CI 1. 2, 4.0) and serum creatinine (3.2 µmol/l, 95% CI 2.2, 4.2) increased in SC treated
patients. Taking baseline differences into account, CIPII treated patients had significant lower
concentrations of ALT as compared to patients treated with SC insulin therapy: 3.6 U/l (95% CI
1.2, 6.0). The results of measurements of all clinical and biochemical parameters performed
at baseline and the end of the study and changes within and differences between groups are
presented in the Appendix 3.
chapter 5part 2
Patient flowchart.figure 1
eligible patients that received information (n=335)
included (n=190)
cipii therapy (n=40)sc insulin therapy (n=150)• mdi (n=75)• csii (n=75)
excluded after visit 2 (n=1)• egfr <40 ml/min
excluded after visit 2 (n=5)• c-peptide > 0.2 nmol/l (n=4)• egfr < 40 ml/min (n=1)
discontinued study (withdrew consent) (n=1)
completed study and included in analysis (n=144)• mdi (n=70)• csii (n=74)
completed study and included in analysis (n=39)
excluded (n=145)• not meeting inclusion criteria (n=11) - psychiatric illness (n=4) - hbA1c < 7.0% (n=3) - predison use (n=2) - non-compliant (n=1)• declined to participate (n=46)• not asked for participation due to logistic reasons (n=88)
86 87
chapter 5part 2
Differences between treatment groups with 95%CI and the non-inferiority interval.figure 2
Error bars indicate the 2-sided 95% CI. The blue dashed line at x=Δ indicates the pre-defined non-inferiority margin for the difference between CIPII and SC insulin treated patients of -0.5%. A: mean difference (95% CI) between CIPII and SC.
Baseline characteristics.table 1
Data are presented as n (%), mean (SD) or median [IQR]. Variables may not add up because of rounding off. *p<0.05 as compared to CIPII, P-values are based on appropriate parametric and non-parametric tests. † Defined as the number of hypoglycaemic events < 4 (grade 1) and < 3.5 (grade 2) during the last 14 days. Abbreviations: ALT; alanine aminotransferase, BMI; Body Mass Index, CIPII; continuous intraperitoneal infusion, SC; subcutaneous. a based on n=32 (CIPII) and n=116 (SC).
Change in glycaemic parameters within- and difference between groups. table 2
Data are means (95% CI) differences within the groups and mean between the (SC vs CIPII insulin therapy) groups adjusted for baseline differences. *p<0.05. † Defined as the number of blood glucose value <4.0 mmol/l during the last 2 weeks ‡ Defined as the number of blood glucose value <3.5 mmol/l during the last 2 weeks. Abbreviations: CIPII; continuous intraperitoneal infusion, SC; subcutaneous. a based on n=36 (CIPII) and n=137 (SC).
MDI and CSII versus CIPIIIn comparison with the CIPII group, MDI and CSII users had a lower HbA1c (-0.29% (95% CI
-0.54, -0.04) for MDI users and -0.26% (95% CI -0.5, -0.01) for CSII users, respectively) and
spent less time in hyperglycemia (-10.3%, (95% CI -17.6, -3.0) for MDI users and -8.6% (95% CI
-15.5, -1.7) for CSII users, respectively) after adjustment for baseline differences. In addition,
MDI users spent 8.2% (95% CI 2.0, 14.5) more time in the euglycaemic range than CIPII treated
patients. Besides higher concentrations of ALT (4.0 U/l, 95% CI 0.8, 7.2 for MDI users and 3.2
U/l, 95% CI 0.1, 6.4 for CSII users, respectively) there were no other differences with respect to
clinical and biochemical parameters (see Appendix 4).
86 87
chapter 5part 2
Differences between treatment groups with 95%CI and the non-inferiority interval.figure 2
Error bars indicate the 2-sided 95% CI. The blue dashed line at x=Δ indicates the pre-defined non-inferiority margin for the difference between CIPII and SC insulin treated patients of -0.5%. A: mean difference (95% CI) between CIPII and SC.
Baseline characteristics.table 1
Data are presented as n (%), mean (SD) or median [IQR]. Variables may not add up because of rounding off. *p<0.05 as compared to CIPII, P-values are based on appropriate parametric and non-parametric tests. † Defined as the number of hypoglycaemic events < 4 (grade 1) and < 3.5 (grade 2) during the last 14 days. Abbreviations: ALT; alanine aminotransferase, BMI; Body Mass Index, CIPII; continuous intraperitoneal infusion, SC; subcutaneous. a based on n=32 (CIPII) and n=116 (SC).
Change in glycaemic parameters within- and difference between groups. table 2
Data are means (95% CI) differences within the groups and mean between the (SC vs CIPII insulin therapy) groups adjusted for baseline differences. *p<0.05. † Defined as the number of blood glucose value <4.0 mmol/l during the last 2 weeks ‡ Defined as the number of blood glucose value <3.5 mmol/l during the last 2 weeks. Abbreviations: CIPII; continuous intraperitoneal infusion, SC; subcutaneous. a based on n=36 (CIPII) and n=137 (SC).
MDI and CSII versus CIPIIIn comparison with the CIPII group, MDI and CSII users had a lower HbA1c (-0.29% (95% CI
-0.54, -0.04) for MDI users and -0.26% (95% CI -0.5, -0.01) for CSII users, respectively) and
spent less time in hyperglycemia (-10.3%, (95% CI -17.6, -3.0) for MDI users and -8.6% (95% CI
-15.5, -1.7) for CSII users, respectively) after adjustment for baseline differences. In addition,
MDI users spent 8.2% (95% CI 2.0, 14.5) more time in the euglycaemic range than CIPII treated
patients. Besides higher concentrations of ALT (4.0 U/l, 95% CI 0.8, 7.2 for MDI users and 3.2
U/l, 95% CI 0.1, 6.4 for CSII users, respectively) there were no other differences with respect to
clinical and biochemical parameters (see Appendix 4).
88 89
Discussion
CIPII is non-inferior to SC insulin therapy with respect to HbA1c among T1DM patients in poor
glycaemic control. CIPII treated patients spent more time in the hyperglycemia and less in
euglycemia as compared to patients using SC insulin therapy. Furthermore, besides lower ALT
concentrations among CIPII treated patients, there were no other differences in clinical and
biochemical parameters between T1DM patients treated with CIPII and SC insulin.
This is the first study to compare the effects of long-term CIPII and SC insulin administration in
a large population of poorly regulated T1DM patients receiving usual care. Since CIPII is a last-
resort treatment option for T1DM, the group of CIPII treated patients is considered selected
and more complex as compared to SC treated patients. This is emphasized by the higher
frequency of microvascular complications and more hyperglycaemic profile among CIPII
treated patients, as compared to SC treated patients, found at baseline in the current study.
Although groups were matched on age and gender, patients were on therapy for
>4 years, measurements were performed with a 26-week interval and outcomes were adjusted
for baseline differences: the non-randomized design remains a limitation of the present study.
In particular the complexity of the CIPII treated group, consisting of both patients with high
HbA1c as well as frequent hypoglycaemic episodes due to various causes, and the modest
number of available patients necessitated pragmatic measures in the study design. In order
to reflect the heterogeneous nature of the CIPII group, a lower HbA1c inclusion criterion for
SC treated patients was chosen. And although groups were well matched on age, gender,
HbA1c and hypoglycaemic episodes at baseline, differences between groups that are known
to influence glycaemic control, such as quality of life which is known to be lower among
CIPII treated patients, could still be present 11,12. Although hypothetical, the presence of such
(unmeasured) differences between groups may have caused a (slight) underestimation of the
effect of CIPII on glycaemic control. This would also be in line with the fact that superiority of
CIPII, above SC insulin, therapy was only found in previous studies with a cross-over design,
which minimize inter-patient variability and looks only at intra-patient changes, and not in
studies with a parallel design 6–8. While fully acknowledging these limitations, we feel that the
current design is the best available for the present study objective given the real-life, clinical
restrictions.
According to the study protocol, the HbA1c difference between both treatment groups was
assessed using a non-inferiority method. Although the HbA1c difference of -0.27% (95% CI
-0.46, -0.09) between CIPII and SC treated patients was negative, the 95% CI remained above
the predefined margin of -0.5%. Therefore it is concluded that CIPII is non-inferior to SC insulin
therapy with respect to HbA1c in the treatment of T1DM.
The present study expands current knowledge regarding CIPII as a treatment modality for
selected patients with T1DM. The effects of CIPII have been described previously in three
randomized studies. After 6 months of cross-over treatment with CIPII and SC insulin, Haardt
et al. reported a difference of 1.28% in favor of CIPII, with a reduction of glycaemic fluctuations
and hypoglycaemic episodes 8. In the 6-month parallel study by Selam et al. there were no
differences between the SC and CIPII study group 7. Among the 24 T1DM patients studied in a
cross-over by Logtenberg et al. there was a HbA1c decrease of 0.76%, with 11% more time spent
in euglycemia and without a change in hypoglycaemic events, in favor of CIPII 6. Subsequent
observational studies among CIPII treated patients found stabilisation of the HbA1c during
long-term follow-up at an equal or lower level than before initiation of CIPII 9,10,13,14.
Although ALT concentrations were still within the normal range and the other liver enzymes
were stable, this finding is remarkable. It might be hypothesized that, since IP insulin
administration results in higher hepatic insulin concentrations than SC insulin administration
this leads to altered hepatic metabolism secondary to higher insulinization 2,3,15.
At present, the costs of CIPII therapy seems to outweighs the advantages of CIPII with regard
to glycaemic regulation for the majority of patients and health care systems 12. Nevertheless,
based on the short-term positive effects found in previous studies, including HbA1c
improvements, less hypoglycaemic episodes and improved quality of life, and the findings
of the present study among long-term CIPII-treated patients we advocate that CIPII using an
implantable pump should be seen a valuable and feasible last-resort treatment option for selected
patients with T1DM who are unable to reach glycaemic control with SC insulin therapy 6,8,12,14.
Conclusions
For the long-term treatment of poorly regulated patients with T1DM, CIPII is non-inferior to
SC insulin therapy with respect to HbA1c. Except for lower ALT concentrations among CIPII
treated patients within the normal range, there are no differences in clinical and biochemical
parameters. This study supports the effectiveness of long-term CIPII therapy as last-resort
treatment in T1DM.
chapter 5part 2
88 89
Discussion
CIPII is non-inferior to SC insulin therapy with respect to HbA1c among T1DM patients in poor
glycaemic control. CIPII treated patients spent more time in the hyperglycemia and less in
euglycemia as compared to patients using SC insulin therapy. Furthermore, besides lower ALT
concentrations among CIPII treated patients, there were no other differences in clinical and
biochemical parameters between T1DM patients treated with CIPII and SC insulin.
This is the first study to compare the effects of long-term CIPII and SC insulin administration in
a large population of poorly regulated T1DM patients receiving usual care. Since CIPII is a last-
resort treatment option for T1DM, the group of CIPII treated patients is considered selected
and more complex as compared to SC treated patients. This is emphasized by the higher
frequency of microvascular complications and more hyperglycaemic profile among CIPII
treated patients, as compared to SC treated patients, found at baseline in the current study.
Although groups were matched on age and gender, patients were on therapy for
>4 years, measurements were performed with a 26-week interval and outcomes were adjusted
for baseline differences: the non-randomized design remains a limitation of the present study.
In particular the complexity of the CIPII treated group, consisting of both patients with high
HbA1c as well as frequent hypoglycaemic episodes due to various causes, and the modest
number of available patients necessitated pragmatic measures in the study design. In order
to reflect the heterogeneous nature of the CIPII group, a lower HbA1c inclusion criterion for
SC treated patients was chosen. And although groups were well matched on age, gender,
HbA1c and hypoglycaemic episodes at baseline, differences between groups that are known
to influence glycaemic control, such as quality of life which is known to be lower among
CIPII treated patients, could still be present 11,12. Although hypothetical, the presence of such
(unmeasured) differences between groups may have caused a (slight) underestimation of the
effect of CIPII on glycaemic control. This would also be in line with the fact that superiority of
CIPII, above SC insulin, therapy was only found in previous studies with a cross-over design,
which minimize inter-patient variability and looks only at intra-patient changes, and not in
studies with a parallel design 6–8. While fully acknowledging these limitations, we feel that the
current design is the best available for the present study objective given the real-life, clinical
restrictions.
According to the study protocol, the HbA1c difference between both treatment groups was
assessed using a non-inferiority method. Although the HbA1c difference of -0.27% (95% CI
-0.46, -0.09) between CIPII and SC treated patients was negative, the 95% CI remained above
the predefined margin of -0.5%. Therefore it is concluded that CIPII is non-inferior to SC insulin
therapy with respect to HbA1c in the treatment of T1DM.
The present study expands current knowledge regarding CIPII as a treatment modality for
selected patients with T1DM. The effects of CIPII have been described previously in three
randomized studies. After 6 months of cross-over treatment with CIPII and SC insulin, Haardt
et al. reported a difference of 1.28% in favor of CIPII, with a reduction of glycaemic fluctuations
and hypoglycaemic episodes 8. In the 6-month parallel study by Selam et al. there were no
differences between the SC and CIPII study group 7. Among the 24 T1DM patients studied in a
cross-over by Logtenberg et al. there was a HbA1c decrease of 0.76%, with 11% more time spent
in euglycemia and without a change in hypoglycaemic events, in favor of CIPII 6. Subsequent
observational studies among CIPII treated patients found stabilisation of the HbA1c during
long-term follow-up at an equal or lower level than before initiation of CIPII 9,10,13,14.
Although ALT concentrations were still within the normal range and the other liver enzymes
were stable, this finding is remarkable. It might be hypothesized that, since IP insulin
administration results in higher hepatic insulin concentrations than SC insulin administration
this leads to altered hepatic metabolism secondary to higher insulinization 2,3,15.
At present, the costs of CIPII therapy seems to outweighs the advantages of CIPII with regard
to glycaemic regulation for the majority of patients and health care systems 12. Nevertheless,
based on the short-term positive effects found in previous studies, including HbA1c
improvements, less hypoglycaemic episodes and improved quality of life, and the findings
of the present study among long-term CIPII-treated patients we advocate that CIPII using an
implantable pump should be seen a valuable and feasible last-resort treatment option for selected
patients with T1DM who are unable to reach glycaemic control with SC insulin therapy 6,8,12,14.
Conclusions
For the long-term treatment of poorly regulated patients with T1DM, CIPII is non-inferior to
SC insulin therapy with respect to HbA1c. Except for lower ALT concentrations among CIPII
treated patients within the normal range, there are no differences in clinical and biochemical
parameters. This study supports the effectiveness of long-term CIPII therapy as last-resort
treatment in T1DM.
chapter 5part 2
90 91
1 Renard E, Schaepelynck-Bélicar P, EVADIAC Group. Implantable insulin pumps. A position statement about their clinical use. Diabetes Metab 2007; 33: 158–66.2 Giacca A, Caumo A, Galimberti G, et al. Peritoneal and subcutaneous absorption of insulin in type I diabetic subjects. J Clin Endocrinol Metab 1993; 77: 738–42.3 Bratusch-Marrain PR, Waldhäusl WK, Gasić S, Hofer A. Hepatic disposal of biosynthetic human insulin and porcine C-peptide in humans. Metabolism 1984; 33: 151–7.4 Nathan DM, Dunn FL, Bruch J, et al. Postprandial insulin profiles with implantable pump therapy may explain decreased frequency of severe hypoglycemia, compared with intensive subcutaneous regimens, in insulin-dependent diabetes mellitus patients. Am J Med 1996; 100: 412–7.5 Schaepelynck Bélicar P, Vague P, Lassmann-Vague V. Reproducibility of plasma insulin kinetics during intraperitoneal insulin treatment by programmable pumps. Diabetes Metab 2003; 29: 344–8.6 Logtenberg SJ, Kleefstra N, Houweling ST, et al. Improved glycemic control with intraperitoneal versus subcutaneous insulin in type 1 diabetes: a randomized controlled trial. Diabetes Care 2009; 32: 1372–7.7 Selam JL, Raccah D, Jean-Didier N, Lozano JL, Waxman K, Charles MA. Randomized comparison of metabolic control achieved by intraperitoneal insulin infusion with implantable pumps versus intensive subcutaneous insulin therapy in type I diabetic patients. Diabetes Care 1992; 15: 53–8.8 Haardt MJ, Selam JL, Slama G, et al. A cost-benefit comparison of intensive diabetes management with implantable pumps versus multiple subcutaneous injections in patients with type I diabetes. Diabetes Care 1994; 17: 847–51.9 Schaepelynck P, Renard E, Jeandidier N, et al. A recent survey confirms the efficacy and the safety of implanted insulin pumps during long-term use in poorly controlled type 1 diabetes patients. Diabetes Technol Ther 2011; 13: 657–60.10 Logtenberg SJJ, van Ballegooie E, Israêl-Bultman H, van Linde A, Bilo HJG. Glycaemic control, health status and treat- ment satisfaction with continuous intraperitoneal insulin infusion. Neth J Med 2007; 65: 65–70.11 DeVries JH, Eskes SA, Snoek FJ, et al. Continuous intraperitoneal insulin infusion in patients with ‘brittle’ diabetes: favourable effects on glycaemic control and hospital stay. Diabet Med J Br Diabet Assoc 2002; 19: 496–501.12 Logtenberg SJ, Kleefstra N, Houweling ST, Groenier KH, Gans RO, Bilo HJ. Health-related quality of life, treatment satisfaction, and costs associated with intraperitoneal versus subcutaneous insulin administration in type 1 diabetes: a randomized controlled trial. Diabetes Care 2010; 33: 1169–72.13 Gin H, Renard E, Melki V, et al. Combined improvements in implantable pump technology and insulin stability allow safe and effective long term intraperitoneal insulin delivery in type 1 diabetic patients: the EVADIAC experience. Diabetes Metab 2003; 29: 602–7.14 Van Dijk PR, Logtenberg SJ, Groenier KH, Gans RO, Kleefstra N, Bilo HJ. Continuous intraperitoneal insulin infusion in type 1 diabetes: a 6-year post-trial follow-up. BMC Endocr Disord 2014; 14: 30.15 Selam JL, Bergman RN, Raccah D, Jean-Didier N, Lozano J, Charles MA. Determination of portal insulin absorption from peritoneum via novel nonisotopic method. Diabetes 1990; 39: 1361–5.
chapter 5part 2
references
90 91
1 Renard E, Schaepelynck-Bélicar P, EVADIAC Group. Implantable insulin pumps. A position statement about their clinical use. Diabetes Metab 2007; 33: 158–66.2 Giacca A, Caumo A, Galimberti G, et al. Peritoneal and subcutaneous absorption of insulin in type I diabetic subjects. J Clin Endocrinol Metab 1993; 77: 738–42.3 Bratusch-Marrain PR, Waldhäusl WK, Gasić S, Hofer A. Hepatic disposal of biosynthetic human insulin and porcine C-peptide in humans. Metabolism 1984; 33: 151–7.4 Nathan DM, Dunn FL, Bruch J, et al. Postprandial insulin profiles with implantable pump therapy may explain decreased frequency of severe hypoglycemia, compared with intensive subcutaneous regimens, in insulin-dependent diabetes mellitus patients. Am J Med 1996; 100: 412–7.5 Schaepelynck Bélicar P, Vague P, Lassmann-Vague V. Reproducibility of plasma insulin kinetics during intraperitoneal insulin treatment by programmable pumps. Diabetes Metab 2003; 29: 344–8.6 Logtenberg SJ, Kleefstra N, Houweling ST, et al. Improved glycemic control with intraperitoneal versus subcutaneous insulin in type 1 diabetes: a randomized controlled trial. Diabetes Care 2009; 32: 1372–7.7 Selam JL, Raccah D, Jean-Didier N, Lozano JL, Waxman K, Charles MA. Randomized comparison of metabolic control achieved by intraperitoneal insulin infusion with implantable pumps versus intensive subcutaneous insulin therapy in type I diabetic patients. Diabetes Care 1992; 15: 53–8.8 Haardt MJ, Selam JL, Slama G, et al. A cost-benefit comparison of intensive diabetes management with implantable pumps versus multiple subcutaneous injections in patients with type I diabetes. Diabetes Care 1994; 17: 847–51.9 Schaepelynck P, Renard E, Jeandidier N, et al. A recent survey confirms the efficacy and the safety of implanted insulin pumps during long-term use in poorly controlled type 1 diabetes patients. Diabetes Technol Ther 2011; 13: 657–60.10 Logtenberg SJJ, van Ballegooie E, Israêl-Bultman H, van Linde A, Bilo HJG. Glycaemic control, health status and treat- ment satisfaction with continuous intraperitoneal insulin infusion. Neth J Med 2007; 65: 65–70.11 DeVries JH, Eskes SA, Snoek FJ, et al. Continuous intraperitoneal insulin infusion in patients with ‘brittle’ diabetes: favourable effects on glycaemic control and hospital stay. Diabet Med J Br Diabet Assoc 2002; 19: 496–501.12 Logtenberg SJ, Kleefstra N, Houweling ST, Groenier KH, Gans RO, Bilo HJ. Health-related quality of life, treatment satisfaction, and costs associated with intraperitoneal versus subcutaneous insulin administration in type 1 diabetes: a randomized controlled trial. Diabetes Care 2010; 33: 1169–72.13 Gin H, Renard E, Melki V, et al. Combined improvements in implantable pump technology and insulin stability allow safe and effective long term intraperitoneal insulin delivery in type 1 diabetic patients: the EVADIAC experience. Diabetes Metab 2003; 29: 602–7.14 Van Dijk PR, Logtenberg SJ, Groenier KH, Gans RO, Kleefstra N, Bilo HJ. Continuous intraperitoneal insulin infusion in type 1 diabetes: a 6-year post-trial follow-up. BMC Endocr Disord 2014; 14: 30.15 Selam JL, Bergman RN, Raccah D, Jean-Didier N, Lozano J, Charles MA. Determination of portal insulin absorption from peritoneum via novel nonisotopic method. Diabetes 1990; 39: 1361–5.
chapter 5part 2
references
92 93
chapter 5part 2
appe
ndix
1Ba
selin
e cha
ract
erist
ics.
Dat
a are
pre
sent
ed as
n (%
), m
ean
(SD
) or m
edia
n [IQ
R]. *
p<0.
05 as
com
pare
d to
CIP
II, †
p<0
.05 f
or M
DI v
ersu
s CSI
I. P-v
alue
s are
bas
ed o
n ap
prop
riate
par
amet
ric an
d no
n-pa
ram
etric
test
s. Re
tinop
athy
, ne
urop
athy
and
neph
ropa
thy c
ateg
orie
s do
not a
dd u
p to
micr
ovas
cula
r cat
egor
y as p
rese
nted
in Ta
ble 1
. Abb
revi
atio
ns: A
LT; a
lani
ne am
inot
rans
fera
se, A
ST; a
spar
tate
amin
otra
nsfe
rase
, BM
I; bo
dy
mas
s ind
ex, C
SII;
cont
inuo
us in
trape
riton
eal i
nsul
in in
fusio
n, C
IPII;
cont
inuo
us in
trape
riton
eal i
nfus
ion,
Gam
ma-
GT; G
amm
a-gl
utam
yl tr
ansp
eptid
ase,
HD
L; h
igh
dens
ity li
popr
otei
n, LD
L; lo
w d
ensit
y lip
opro
tein
, MD
I; m
ultip
le d
aily
inje
ctio
ns, S
C; su
bcut
aneo
us. a b
ased
on
n=32
(CIP
II), n
=56 (
MD
I) an
d n=
69 (C
SII).
92 93
chapter 5part 2
appe
ndix
1Ba
selin
e cha
ract
erist
ics.
Dat
a are
pre
sent
ed as
n (%
), m
ean
(SD
) or m
edia
n [IQ
R]. *
p<0.
05 as
com
pare
d to
CIP
II, †
p<0
.05 f
or M
DI v
ersu
s CSI
I. P-v
alue
s are
bas
ed o
n ap
prop
riate
par
amet
ric an
d no
n-pa
ram
etric
test
s. Re
tinop
athy
, ne
urop
athy
and
neph
ropa
thy c
ateg
orie
s do
not a
dd u
p to
micr
ovas
cula
r cat
egor
y as p
rese
nted
in Ta
ble 1
. Abb
revi
atio
ns: A
LT; a
lani
ne am
inot
rans
fera
se, A
ST; a
spar
tate
amin
otra
nsfe
rase
, BM
I; bo
dy
mas
s ind
ex, C
SII;
cont
inuo
us in
trape
riton
eal i
nsul
in in
fusio
n, C
IPII;
cont
inuo
us in
trape
riton
eal i
nfus
ion,
Gam
ma-
GT; G
amm
a-gl
utam
yl tr
ansp
eptid
ase,
HD
L; h
igh
dens
ity li
popr
otei
n, LD
L; lo
w d
ensit
y lip
opro
tein
, MD
I; m
ultip
le d
aily
inje
ctio
ns, S
C; su
bcut
aneo
us. a b
ased
on
n=32
(CIP
II), n
=56 (
MD
I) an
d n=
69 (C
SII).
94 95
chapter 5part 2
Resu
lts of
the p
er p
roto
col a
nd in
tent
ion
to tr
eat a
naly
sis fo
r the
prim
ary o
utco
me.
appe
ndix
2
Dat
a are
mea
ns (S
D) a
nd d
iffer
ence
bet
wee
n m
eans
(95%
CI).
Dat
a are
mea
ns (S
D) a
nd d
iffer
ence
bet
wee
n m
eans
(95%
CI).
Inte
ntio
n to
trea
t ana
lysis
(n=1
84)
Per p
roto
col a
naly
sis (n
=183
)
appe
ndix
3Ou
tcom
es d
urin
g bas
elin
e and
fina
l visi
t, cha
nges
with
in- a
nd d
iffer
ence
s bet
wee
n gr
oups
.
Dat
a are
pre
sent
ed as
n (%
), m
ean
(SD
) or m
edia
n [IQ
R]. *
p<0.
05 a b
ased
on
n=11
6 and
n=3
2 b bas
ed o
n n=
137 a
nd n
=36.
† D
efine
d as
the n
umbe
r of b
lood
glu
cose
valu
e <4.
0 m
mol
/l du
ring
the l
ast 2
wee
ks
‡ D
efine
d as
the n
umbe
r of b
lood
glu
cose
valu
e <3.
5 mm
ol/l
durin
g th
e las
t 2 w
eeks
. ¥ D
efine
d as
the n
umbe
r of h
ypog
lyca
emic
episo
des r
equi
ring
third
par
ty h
elp
or lo
sing
cons
cious
ness
dur
ing
the l
ast
2 wee
ks. A
bbre
viat
ions
: ALT
; ala
nine
amin
otra
nsfe
rase
, AST
; asp
arta
te am
inot
rans
fera
se, B
MI;
body
mas
s ind
ex, C
IPII;
cont
inuo
us in
trape
riton
eal i
nfus
ion,
Gam
ma-
GT; G
amm
a-gl
utam
yl tr
ansp
eptid
ase,
HD
L; h
igh
dens
ity li
popr
otei
n, LD
L; lo
w d
ensit
y lip
opro
tein
, SC;
subc
utan
eous
. † D
efine
d as
a nu
mbe
r of b
lood
glu
cose
valu
e <4.
0 m
mol
/l du
ring
the l
ast 2
wee
ks.
94 95
chapter 5part 2
Resu
lts of
the p
er p
roto
col a
nd in
tent
ion
to tr
eat a
naly
sis fo
r the
prim
ary o
utco
me.
appe
ndix
2
Dat
a are
mea
ns (S
D) a
nd d
iffer
ence
bet
wee
n m
eans
(95%
CI).
Dat
a are
mea
ns (S
D) a
nd d
iffer
ence
bet
wee
n m
eans
(95%
CI).
Inte
ntio
n to
trea
t ana
lysis
(n=1
84)
Per p
roto
col a
naly
sis (n
=183
)
appe
ndix
3Ou
tcom
es d
urin
g bas
elin
e and
fina
l visi
t, cha
nges
with
in- a
nd d
iffer
ence
s bet
wee
n gr
oups
.
Dat
a are
pre
sent
ed as
n (%
), m
ean
(SD
) or m
edia
n [IQ
R]. *
p<0.
05 a b
ased
on
n=11
6 and
n=3
2 b bas
ed o
n n=
137 a
nd n
=36.
† D
efine
d as
the n
umbe
r of b
lood
glu
cose
valu
e <4.
0 m
mol
/l du
ring
the l
ast 2
wee
ks
‡ D
efine
d as
the n
umbe
r of b
lood
glu
cose
valu
e <3.
5 mm
ol/l
durin
g th
e las
t 2 w
eeks
. ¥ D
efine
d as
the n
umbe
r of h
ypog
lyca
emic
episo
des r
equi
ring
third
par
ty h
elp
or lo
sing
cons
cious
ness
dur
ing
the l
ast
2 wee
ks. A
bbre
viat
ions
: ALT
; ala
nine
amin
otra
nsfe
rase
, AST
; asp
arta
te am
inot
rans
fera
se, B
MI;
body
mas
s ind
ex, C
IPII;
cont
inuo
us in
trape
riton
eal i
nfus
ion,
Gam
ma-
GT; G
amm
a-gl
utam
yl tr
ansp
eptid
ase,
HD
L; h
igh
dens
ity li
popr
otei
n, LD
L; lo
w d
ensit
y lip
opro
tein
, SC;
subc
utan
eous
. † D
efine
d as
a nu
mbe
r of b
lood
glu
cose
valu
e <4.
0 m
mol
/l du
ring
the l
ast 2
wee
ks.
96 97
chapter 5part 2
appe
ndix
4Ou
tcom
es d
urin
g bas
elin
e and
fina
l visi
t, cha
nges
with
in th
e MDI
and
CSII
grou
ps an
d di
ffere
nces
with
the C
IPII
grou
p.
Dat
a are
pre
sent
ed as
n (%
), m
ean
(SD
) or m
edia
n [IQ
R]. *
p<0.
05 a b
ased
on
n=11
6 and
n=3
2 b bas
ed o
n n=
137 a
nd n
=36.
† D
efine
d as
the n
umbe
r of b
lood
glu
cose
valu
e <4.
0 m
mol
/l du
ring
the l
ast 2
wee
ks
‡ D
efine
d as
the n
umbe
r of b
lood
glu
cose
valu
e <3.
5 mm
ol/l
durin
g th
e las
t 2 w
eeks
. ¥ D
efine
d as
the n
umbe
r of h
ypog
lyca
emic
episo
des r
equi
ring
third
par
ty h
elp
or lo
sing
cons
cious
ness
dur
ing
the l
ast
2 wee
ks. A
bbre
viat
ions
: ALT
; ala
nine
amin
otra
nsfe
rase
, AST
; asp
arta
te am
inot
rans
fera
se, B
MI;
body
mas
s ind
ex, C
SII;
cont
inuo
us in
trape
riton
eal i
nsul
in in
fusio
n, C
IPII;
cont
inuo
us in
trape
riton
eal i
nfus
ion,
Ga
mm
a-GT
; Gam
ma-
glut
amyl
tran
spep
tidas
e, H
DL;
hig
h de
nsity
lipo
prot
ein,
LDL;
low
den
sity l
ipop
rote
in, M
DI;
mul
tiple
dai
ly in
ject
ions
.
96 97
chapter 5part 2
appe
ndix
4Ou
tcom
es d
urin
g bas
elin
e and
fina
l visi
t, cha
nges
with
in th
e MDI
and
CSII
grou
ps an
d di
ffere
nces
with
the C
IPII
grou
p.
Dat
a are
pre
sent
ed as
n (%
), m
ean
(SD
) or m
edia
n [IQ
R]. *
p<0.
05 a b
ased
on
n=11
6 and
n=3
2 b bas
ed o
n n=
137 a
nd n
=36.
† D
efine
d as
the n
umbe
r of b
lood
glu
cose
valu
e <4.
0 m
mol
/l du
ring
the l
ast 2
wee
ks
‡ D
efine
d as
the n
umbe
r of b
lood
glu
cose
valu
e <3.
5 mm
ol/l
durin
g th
e las
t 2 w
eeks
. ¥ D
efine
d as
the n
umbe
r of h
ypog
lyca
emic
episo
des r
equi
ring
third
par
ty h
elp
or lo
sing
cons
cious
ness
dur
ing
the l
ast
2 wee
ks. A
bbre
viat
ions
: ALT
; ala
nine
amin
otra
nsfe
rase
, AST
; asp
arta
te am
inot
rans
fera
se, B
MI;
body
mas
s ind
ex, C
SII;
cont
inuo
us in
trape
riton
eal i
nsul
in in
fusio
n, C
IPII;
cont
inuo
us in
trape
riton
eal i
nfus
ion,
Ga
mm
a-GT
; Gam
ma-
glut
amyl
tran
spep
tidas
e, H
DL;
hig
h de
nsity
lipo
prot
ein,
LDL;
low
den
sity l
ipop
rote
in, M
DI;
mul
tiple
dai
ly in
ject
ions
.